Method for producing a drug delivery system

ABSTRACT

The present invention relates to a method for producing a drug delivery system. The method comprises the steps of screen-printing a base paste, and curing the base paste. Furthermore, the method comprises the steps of screen-printing a first paste separate to the base paste, and curing the first paste.

This application is a national phase of International Application No.PCT/EP2017/084828 filed Dec. 29, 2017 and published in the Englishlanguage, which is hereby incorporated herein by reference in itsentirety.

1. FIELD OF THE INVENTION

The present invention relates to a method for producing a drug deliverysystem, the drug delivery system preferably being for a controlled,further preferred systemic administration of one or more activepharmaceutical ingredients to a body. Furthermore, the invention relatesto a system for producing a drug delivery system.

2. TECHNICAL BACKGROUND

A drug, or a pharmaceutical drug, is commonly used for diagnosing,curing, treating or preventing diseases. An active pharmaceuticalingredient (API) may be the part of any drug that produces its effects.Some drugs may have multiple APIs to treat different symptoms or act indifferent ways. Thus, one or more APIs may be delivered by a drug. Thedelivery of drugs, or drug delivery, may refer to the transportation ofa pharmaceutical compound into the body of a patient as needed to safelyachieve its desired (therapeutic) effect. The delivery or administrationof a drug into the body of a patient may be performed in various ways.The routes of administration include, among others, the intravenous(into the blood compartment through the puncture of a vein) and oralroute (through the mouth of the patient, e.g. to enter via the oralmucosa or pass on into the gastrointestinal tract to reach the bloodcompartment via the gastric or intestinal mucosa). Drugs can further beadministered by inhalation, by injection into tissues (e.g.,subcutaneous, intramuscular) or by topical application (e.g., creams foruse on the skin). Drugs can be provided in different dosage forms. Thedosage forms may comprise, among others, pills, tablets, capsules,solutions, dispersions, emulsions, implants.

A tablet may be a pharmaceutical dosage form. A tablet may be a solidunit dosage form of a pharmaceutical drug comprising an API, with orwithout suitable excipients. Tablets may be produced either by moldingor by compression. Upon manufacturing of a tablet, the main guideline iscommonly to ensure that the appropriate amount of active pharmaceuticalingredient(s) is in each tablet. Therefore, all ingredients should bewell mixed. Thereby, a homogeneous mixture of the ingredients isobtained. A particular amount of the mixture may then be compressed inorder to obtain a tablet. Thus, the API is typically homogeneouslydistributed throughout the tablet, or parts of it.

Upon application of a tablet, for example upon oral administration, thetablet may dissolve and thereby the API may be released. It then passesthe intestinal mucous membrane to reach the blood compartment andfinally the tissue of action. With the commonly produced drug deliverysystems, the concentration of the API within the blood compartment istypically such that, for a particular period of time only, it is abovethe efficacy threshold of the given API. During this period, the releaseof the API out of the drug delivery system into the gastrointestinaltract is however typically much higher than actually required, wherebythe excess amount of the API may (i) not pass the membrane in sufficientamounts and be picked up by the body and, thus, may be excreted of (ii)may reach the blood compartment/the tissue to result in toxic effects.

According to the respective background of the drug application, or theparticular therapeutic program, it may be desirable to have a particularrelease profile of the API. It may, for example, be desirable to releasethe API at the constant rate over a prolonged period of time. In otherscenarios, it may be desirable to provide for a particularly slowrelease of an API to a body, with a release rate slightly above theefficacy threshold of the API, wherein the rate of release may beapproximately independent of time. In further scenarios, it may bedesirable to release the API at particular intervals, for exampleintermittently over time. In further scenarios, it may be desirable torelease several APIs one after the other, or simultaneously atindividual release rates, with API-specific release profiles.

Release of APIs out of common tablets, which are characterized by ahomogeneous distribution of the APIs due to the requirements and limitsof the conventional manufacturing technologies, is mainly driven by thesize of the disintegrating tablet, in particular, the surface that isexposed to the surrounding fluid. As such it is predefined by the formand size of the tablet and fixed, with for example a high release at thebeginning and lowering over time. The resulting blood/tissueconcentrations of the API may thereby well exceed the respectiveefficacy threshold, in order to obtain a desired period of concentrationabove said threshold.

Such a release profile is particularly disadvantageous for APIs with anarrow therapeutic window (that is little difference between therapeuticand toxic dose). APIs with a narrow therapeutic index (NTI) includeaminoglycosides, ciclosporin, carbamazepine, digoxin, digitoxin,flecainide, lithium, phenytoin, phenobarbital, rifampicin, theophylline,warfarin.

Reference U.S. Pat. No. 3,854,480 describes a drug delivery system forreleasing an active pharmaceutical ingredient at a controlled rate for aprolonged period of time. The drug delivery system thereby comprises asolid inner matrix material having solid particles of the drugdistributed therethrough, and an outer polymeric membrane, which ispermeable and insoluble in body fluids and which surrounds the innermatrix. The outer polymeric membrane thereby continuously meters theflow of drug from the inner matrix material to the exterior of thesystem at a controlled and constant rate over a prolonged period oftime. However, the drug delivery system according to U.S. Pat. No.3,854,480 does not allow for more elaborate release profiles. Further,the administration of an insoluble polymeric membrane to the body of apatient may be disadvantageous.

Reference U.S. Pat. No. 5,674,530 A relates to a drug delivery system,wherein a first water permeable capsule half is filled with a drug andan osmotic agent. Reference US 2010/0068271 A1 relates to osmoticdelivery systems employed in tablets, being divisible into two useablehalf-strength tablets. The release by means of osmotic effects isdependent, among others, on the environment of the drug delivery systemin the patient, making a precise drug release at a desired targetchallenging. Thus, it is difficult to achieve a controlled and precisedrug release with such systems. Furthermore, such systems do not allowfor more elaborate release profiles.

Reference WO 1993/007861 A1 relates to drug delivery systems involvingmicrocapsules or microspheres. Thereby multi-phase microspheres aredescribed to include a molecular compound contained within a fixed oilwithin a polymeric matrix.

The molecular compound may first have to traverse a water-oil barrier,and the polymer barrier of the polymer matrix, before it can diffuse outof the microsphere. Thereby, a constant and fixed rate of delivery of amolecular compound can provided without sacrificing high drug loadingefficiency in the microsphere. However, this prior art system does notallow for more elaborate release profiles.

Reference WO 1999/008662 A1 relates to a drug delivery system suitablefor oral administration that facilitates a two-step release of an activeagent. A drug delivery system disclosed therein comprises a first drugcompartment, a first polymer compartment substantially enveloping thefirst drug compartment, a second drug compartment enveloping the firstpolymer compartment, and a second polymer compartment enveloping thesecond drug compartment. The second polymer compartment, which may be ofone or more water insoluble polymers, controls the release of an activeagent from the second drug compartment. However, this prior art systemdoes not allow for more elaborate release profiles.

The present invention aims at overcoming the disadvantages outlinedabove. Thus, one problem underlying the present invention is to providea method for producing a more efficient drug delivery system which canadvantageously provide for a controlled administration of one or moreactive pharmaceutical ingredients to a body, with anapplication-tailored, therapy-tailored and/or API-specific releaseprofile. A further object of the present invention is to provide amethod for producing a drug delivery system which allows for acontrolled administration of several APIs to a body, such that the APIsare released relative to each other in a defined manner, preferably withdesired API-specific release profiles. A general object of the inventioncan be formulated as to provide an improved technique for producing adrug delivery system, which allows for producing advanced drug deliverysystems with high quality and in great quantities. The advanced drugdelivery system may thereby optimize pharmacokinetics andpharmacodynamics.

These and other objects, which are apparent for the person skilled inthe art from the following description, are solved by a method forproducing a drug delivery system, a drug delivery system, and by systemsfor producing a drug delivery system.

3. SUMMARY OF THE INVENTION

The present invention relates to a method for producing a drug deliverysystem. Said drug delivery system may allow for transporting an activepharmaceutical ingredient (API) in the body of the patient as needed tosafely achieve its desired therapeutic effect. The drug delivery systemmay thereby include an API, or several APIs, or other ingredients suchas vitamins and minerals. The drug delivery system may be a bioerodibledrug delivery system. Thus, the drug delivery system may erode uponapplication thereof to a body of a patient, and may, for example,dissolve upon application, e.g. in the mouth of the patient. The drugdelivery system produced according to the present invention isparticularly suited for a controlled administration of one or more APIsto a body. The body may be the body of a patient, which may be a humanor an animal. Further in particular, the drug delivery system producedaccording to the present invention may be used for oral administrationof one or more APIs to a body, whereby the drug delivery system maydissolve in the mouth of the patient. Thus, with the drug deliverysystem produced according to the present invention, an API can beadministered in a controlled manner, depending on the particular therapyor application case.

The method for producing a drug delivery system according to the presentinvention comprises the step of screen-printing a base paste. The basepaste may include water, polyvinylpyrrolidone, citric acid,hypromellose, stearate, silic acid, glycerol, Hydroxypropyl cellulose,hydroxypropyl methylcellulose, starch, cellulosecrosscaramelose, glycol,crystalline gelatin, collagen, hydroxyapatite, hydrocarbonate, lactide,lactic acid, silica, polaxamers, xylitol, erythritol, ethanol,isopropanol, triacetin, aspartame, sodium bicarbonate, and/or acetone.The viscosity of the base paste may be in the range of 1˜10⁻²-1·10¹⁴mPa·s, preferably in the range of 1·10⁻¹-1·10⁸ mPa·s, further preferredin the range of 1·10⁰-1·10⁷ mPa·s, further preferred in the range of1·10¹-1·10⁶ mPa·s. For screen-printing the base paste, a respectiveprinting mesh may be used, which allows for providing the base paste inaccordance with a desired printing profile, so that for example onlycertain areas of the resulting drug delivery system are formed of thebase paste.

Furthermore, the method comprises the step of curing the base paste.Thereby, the base paste may be cured, such that it hardens. The curingtemperatures and curing times may depend on the composition of the basepaste. For example, the base paste may be cured at a temperature of 30°C. to 180° C., preferably 35° C. to 150° C., further preferred 40° C. to110° C., further preferred 45° C. to 90° C., further preferred 50° C. to70° C. Preferably, curing times of 10 seconds to 1 hour, preferably 30seconds to 30 minutes, preferably 1 minute to 10 minutes may be applied.

Furthermore, the method comprises the step of screen-printing a firstpaste separate to the (preferably cured) base paste. Thus, the firstpaste is provided separate from the base paste. Thereby, the first pasteis arranged separate from the base paste, i.e. preferably without anoverlap, as the first paste may be screen-printed such that it isarranged at locations where the base paste was not screen-printed. Thecomponent(s) of the first paste are not mixed with the component(s) ofthe base paste in a classical manner to form a homogeneous mixture.Instead, the first paste is provided separate to the base paste. Thus,within the resulting drug delivery system, the base paste can bedistinguished from the first paste. The first paste may include[HM₁]water, polyvinylpyrrolidone, citric acid, hypromellose, stearate,silic acid, glycerol, Hydroxypropyl cellulose, hydroxypropylmethylcellulose, starch, cellulosecrosscaramelose, glycol, crystallinegelatin, collagen, hydroxyapatite, hydrocarbonate, lactide, lactic acid,silica, polaxamers, xylitol, erythritol, ethanol, isopropanol,triacetin, aspartame, sodium bicarbonate, and/or acetone. The viscosityof the base paste may be in the range of 1·10⁻²-1·10¹⁴ mPa·s, preferablyin the range of 1·10⁻¹-1·10⁸ mPa·s, further preferred in the range of1·10⁰-1·10⁷ mPa·s, further preferred in the range of 1·10¹-1·10⁶ mPa·s.For screen-printing the first paste, a respective printing mesh may beused, which allows for providing the first paste in accordance with adesired printing profile, so that for example only certain areas of theresulting drug delivery system are formed of the first paste.

Furthermore, the method comprises the step of curing the first paste.The curing temperatures and curing times may depend on the compositionof the first paste. For example, the first paste may be cured at atemperature of 30° C. to 180° C., preferably 35° C. to 150° C., furtherpreferred 40° C. to 110° C., further preferred 45° C. to 90° C., furtherpreferred 50° C. to 70° C. Preferably, curing times of 10 seconds to 1hour, preferably 30 seconds to 30 minutes, preferably 1 minute to 10minutes may be applied. The first paste may be cured together with thebase paste. Alternatively, the screen-printing and curing of the firstpaste may be performed after curing the screen-printed base paste.

Furthermore, according to the present invention, the first pastecomprises a therapeutically effective amount of a first activepharmaceutical ingredient. Accordingly, the first paste may comprise theAPI which is to be delivered or administered by means of the resultingdrug delivery system. The first API may be homogeneously distributedwithin the first paste. The person skilled in the art understands thatthe first paste may comprise several APIs, which may be homogeneouslydistributed within the first paste. Also, the base paste may comprise anactive pharmaceutical ingredient.

The method thus allows for producing and enhanced drug delivery system,whereby the base paste and the first paste may be provided in the drugdelivery system such that it is possible to obtain a particularlydesired release of the first API. By controlling the arrangement of thefirst paste in relation to the base paste during the respectivescreen-printing steps, e.g. by choosing proper printing profiles, it canbe controlled at what time and at which rate the first API is releasedfrom the drug delivery system. This allows for producing a drug deliverysystem with an optimal API release for a controlled administration of agiven API to a body.

The utilization of the screen-printing technique allows for the massproduction of the drug delivery system, at a high precision. Forexample, nano-sized geometries of the first paste, and thus of the firstAPI, can be printed, so that the arrangement of the first API throughoutthe resulting drug delivery system can be controlled at high precision.The screen-printing technique further allows for providing the firstpaste such that is forms a particularly preferred geometrical shape inthe cured state in the resulting drug delivery system. The utilizationof the screen-printing technique further allows for producing severaldrug delivery systems in a parallel manner. For example, whilescreen-printing the base paste, numerous drug delivery systems may beproduced simultaneously by using a respective printer with such a meshwhich allows for printing the base paste to form an array of 100×100tablets, for example. Similarly, also the first paste may be printed toeventually form the array of 100×100 tablets simultaneously. The arrayof 100×100 tablets may also be cured simultaneously.

The resolution of the screen-printing pattern depends on the compositionof the pastes, among others. Preferably, a resolution in the range of 10dpi to 10000 dpi, further preferred 100 dpi to 5000 dpi, furtherpreferred 200 dpi to 2000 dpi, further preferred 500 dpi to 1000 dpi isprovided for, such that the first API can eventually be arranged in thedrug delivery system in a refined manner. Accordingly, two- orthree-dimensional structures formed of the base paste and first paste inthe drug delivery system may feature a resolution in the range of 10 dpito 10000 dpi, further preferred 100 dpi to 5000 dpi, further preferred200 dpi to 2000 dpi, further preferred 500 dpi to 1000 dpi.

Preferably, the drug delivery system is produced layer-by-layer. Thus,in producing the drug delivery system in a layer-by-layer fashion, onelayer may be formed on top of another layer to build up the drugdelivery system. For example, a first layer of the drug delivery systemmay be produced by screen-printing and curing the base paste and thefirst paste, and then a further layer may be produced on top of thefirst layer, and so on. The drug delivery system may be produced using amovable platform, which may be provided underneath a printing screen.After each completion of a layer, the movable platform may be loweredvertically by a respective step size, and then the next layer may beproduced on top thereof. The person skilled in the art understands thatthe arrangement of the (possibly cured) first paste relative to the(possibly cured) base paste may differ in adjacent layers.

In a preferred embodiment, the pastes are screen-printed such that aresulting planar layer of the drug delivery system comprises both thecured base paste and the cured first paste. Accordingly, a planar layerof the resulting drug delivery system may comprise the cured base paste,and the cured first paste separate to the base paste. Thus, both (cured)pastes can be differentiated from another, as no homogeneous mixture isprovided.

Further preferred, the planar layer of the drug delivery system isproduced by screen-printing and curing the base paste to partially formthe planar layer, and screen-printing and curing the first pasteseparate to the base paste to partially form the planar layer.Preferably, by producing the planar layer, the pastes are notscreen-printed in an overlapping manner. Thus, by screen-printing andcuring the base paste, a part of the resulting planar layer may beformed. A further part of the resulting planar layer, preferably theremaining part of the resulting planar layer, may then formed byscreen-printing and curing the first paste. For example, the resultingplanar layer may thus comprise areas where only the base paste isarranged (for example at outer regions of the layer), and further areaswhere only the first paste is arranged (for example at inner regions ofthe layer). The pastes must not form continuous areas, but can formseparate areas, i.e. “islands”.

Further preferred, after finishing the production of the planar layer, afurther planar layer is produced on top of the finished planar layer.Thereby, a different arrangement or printing-profile may be chosen.Thus, a desired three-dimensional arrangement of the first pasterelative to the base paste can be obtained, so that eventually a desiredthree-dimensional distribution of the first API throughout the resultingdrug delivery system can be obtained.

Preferably, the base paste is screen-printed using a screen-printer, andthe first paste is screen-printed using a separate screen-printer. Thus,in a respective production line, several screen-printers may bearranged, which are each configured for printing a single paste, forexample the base paste or the first paste. By inserting or removingindividual printers into or out of the production line, the productionline can be modified to produce different drug delivery system designsaccording to the present invention. Thus, a high flexibility is arrangedfor by this modular setup.

Preferably, the base paste and the first paste are cured with a sharedcuring device. Accordingly, only one curing device is preferably neededin the production line, for producing the drug delivery system. Althoughseveral individual screen-printers may be used, the built may betransferred to the shared curing device for curing the respectivepaste(s). This may allow for cost savings.

Preferably, the (cured) base paste and the (cured) first paste aresoluble in body fluids. As an example, body fluids may include blood, orbody tissue fluids. Body fluids encountered will vary according to theroute of administration. Upon oral intake of the drug delivery system,the composition of the outer layer may determine whether dissolution ofthe drug delivery system will start in the mouth (dissolution in saliva)or later along the journey of the drug delivery system through thegastrointestinal tract, in particular the stomach (acidic milieu), theileum, the jejunum or other places. Likewise, the drug delivery systemproduced according to the present invention may be directly placed intotissues (e.g. subcutaneously, intramuscularly) or body cavities (e.g.pleural space) or into the cerebrospinal fluid spaces. Upon placementinto the ventricles, the drug delivery system may dissolve within thecerebrospinal fluid and any released API may reach the brain tissue.Placement into natural body cavities (e.g. pleural space, peritonealspace) is meant to reach these localizations at high quantities. Anotherpossibility may comprise dissolution within the airways upon inhalation.The person skilled in the art will appreciate that dissolutioncharacteristics of the (cured) pastes and thus of the resulting drugdelivery system may be chosen such that a suitable release of the API isobtained depending on the respective therapy or application. Thereby, arather instant or rather slow dissolution can be chosen.

The (cured) first paste and the (cured) base paste may dissolve in asimilar manner. Preferably, both the base paste and the first paste candissolve in the same body fluid. Therefore, by screen-printing the firstpaste and the base paste separate to one another, and due to thedissolution characteristics thereof, it can be controlled at what timeand at which rate the first API is released from the resulting drugdelivery system. Preferably, the release of the API is determined onlyby the dissolution characteristics of the (cured) pastes and the form orshape of the resulting drug delivery system. No further release agentsare required, such as, e.g., osmotic agents for releasing the API.

Preferably, the pastes are screen-printed such that in the resultingdrug delivery system, the (cured) first paste is inhomogeneouslyarranged in the (cured) base paste. Accordingly, the base paste and thefirst paste are not provided as a homogeneous mixture in the resultingdrug delivery system, but are provided separately from another,preferably in a particular manner, wherein the first paste isinhomogeneously arranged in the base paste. The first paste may beprovided inhomogeneously or discontinuously along one, two or mostpreferred three spatial or orthogonal directions in the base paste. Byarranging the pastes in this manner, the first paste is being arrangedin the resulting drug delivery system in such a controlled and desiredmanner, so that no homogeneous distribution of the first paste (and thusof the first API) is present throughout the resulting drug deliverysystem. Instead, the inhomogeneity is specifically constituted by theparticular arrangement of the pastes. As the base paste and the firstpaste are provided as separate pastes by separately screen-printing thebase paste and the first paste in a preferably non-overlapping manner,the first paste can be arranged inhomogeneously within a matrix formedof the base paste. For example, the amount of the first paste arrangedwithin the base paste may increase gradually along a particulardirection throughout the resulting drug delivery system.

The pastes may be screen-printed such that in the resulting drugdelivery system, the (cured) base paste may be provided or considered asa three-dimensional body, and the (cured) first paste may beinhomogeneously arranged throughout the base paste. Thus, the main bodyof the resulting drug delivery system may be formed of the base pasteand one or more particular parts of the drug delivery system, which maybe only of marginal size, may be formed of the first paste. The basepaste and the first paste may be arranged on a virtual two- orthree-dimensional grid, wherein each pixel of the grid may be occupiedby the base paste or by the first paste. Thus, the first paste ispreferably arranged inhomogeneously in the base paste and thus may beinhomogeneously arranged in the resulting drug delivery system itself.The size or volume of each of such a pixel may be in the range of 1 μm³to 1 cm³, preferably in the range of 10 μm³ to 100 mm³, preferably inthe range of 100 μm³ to 10 mm³, and most preferred of about 1 mm³.

As the common principle of a homogeneous distribution of an APIthroughout the drug delivery system is preferably suspended, it ispossible to provide a particular arrangement of the API in the resultingdrug delivery system to obtain a drug delivery system with a customizedrelease profile of the API. The paste comprising the API may be arrangedsuch that a steady release of the API is obtained, with a release thatpreferably results in a blood-tissue concentration slightly above theefficacy threshold of the API. Thereby, as compared to the commonlyproduced drug delivery systems with a homogeneous distribution of theAPI, an effectively less amount of API is advantageously required withthe preferred drug delivery system produced according to the presentinvention, while the same clinical results are maintained with lowerside-effects.

Preferably, the inhomogeneous distribution of an API in the drugdelivery system produced according to the present invention is utilizedin a standardized manner, whereby a particular arrangement is chosen orset. This concept allows for producing drug delivery systems with theadvantageous release profiles as described herein. The standardization,definition or specification of the arrangement of the pastes and thus,the standardization, definition or specification of the inhomogeneity ofthe API allows for producing such drug delivery systems uniformly inhigh quantity, also in a mass production.

The person skilled in the art understands that by screen-printing andcuring the base paste, processes such as cross-linking within the basepaste may take place, thereby eventually altering the base paste itself.It will be appreciated that the resulting structure of the cured basepaste may still be considered to be essentially formed of the respectivebase paste, although its viscosity may have changed significantly.Accordingly, when reference is made to the base paste in the resultingdrug delivery system, the person skilled in the art understands thatthis base paste may be the respective cured base paste. The same appliesto other pastes.

In a preferred embodiment, the pastes are screen-printed such that inthe resulting drug delivery system the concentration of the first APIvaries throughout the drug delivery system, or further preferred variesthroughout the body defined by the base paste. For example, printingprofiles may be chosen which allow for screen-printing the first pasteat central parts of the drug delivery system only. Thus, particularregions of the resulting drug delivery system may be identified having arather high concentration of the first API, and particular regions maybe identified having a rather low (or even no) concentration of thefirst API. Thereby, whilst taking into consideration the particular formor shape of the drug delivery system, as well as the dissolutioncharacteristics of the base paste and first paste, it can be preciselycontrolled when and how the API is eventually released.

Further preferred, the pastes are screen-printed such that in theresulting drug delivery system the concentration of the first API ishighest at a center, at an edge or at an intermediate region of the drugdelivery system. Thus, for example, if the resulting drug deliverysystem is provided in form of a tablet, the first paste may be arrangedor screen-printed such that a peak concentration of the first API isprovided at the center or a central part of the tablet. Accordingly,upon administration of the tablet and dissolution of the base paste andthe first paste, the release of the first API may increase over time, ormay remain approximately constant over time, also depending on the shapeof the drug delivery system. This allows for obtaining a desired,specific release of the API.

Further preferred, the pastes are screen-printed such that in theresulting drug delivery system a gradient of the concentration of thefirst API increases towards or increases away from a center of a drugdelivery system. For example, the printing profiles may be chosen suchthat the amount of screen-printed first paste increases towards thecenter of the drug delivery system. For example, if the resulting drugdelivery system is provided in form of a spherical tablet, thearrangement of the first paste and thus of the first API may be suchthat the release rate is approximately constant upon application of thedrug delivery system, when the concentration increases towards thecenter of the tablet. By adjusting the concentration profile of the APIthroughout the drug delivery system by adjusting the printing profileduring screen-printing, the release profile of the API can be wellcontrolled.

Further preferred, the pastes are screen-printed such that in theresulting drug delivery system a concentration profile of the first APIthroughout the drug delivery system comprises a smooth transition to anarea of increased concentration. For example, the printing profiles maybe chosen such that the amount of screen-printed first paste increasesgradually towards the center of the drug delivery system. Thus, theconcentration profile may comprise a smooth transition between an areaof low (or possibly no) concentration, and an area of highconcentration. A smooth transition may be defined by the absence ofabrupt or discontinuous steps in the concentration profile. Theconcentration profile may represent the profile of the concentration ofthe first API diagonally across the resulting drug delivery system, forexample from one edge of the drug delivery system to its center, orpossibly extending through the entire drug delivery system. With suchsmooth transitions, it is possible to obtain a smooth onset of therelease of the API upon dissolution of the respective cured paste.

Further preferred, the pastes are screen-printed such that in theresulting drug delivery system a concentration profile of the first APIthroughout the drug delivery system comprises more than one area ofincreased concentration. Thereby, several dosages of the API can beadministered over time with the resulting drug delivery system.Particularly preferred, due to the respective printing profiles duringscreen-printing, the deposition of the first API within the drugdelivery system along the dissolution direction (e.g. from the peripheryto the center) may be discontinuous and repetitive in an onion skin typemanner. In each such shell of the drug delivery system, the first pastemay be provided inhomogeneously, such that a release of the first API ispreferably not starting in an abrupt manner, but can be set such thatthe release starts and/or ends gradually. Thereby, the release of theAPI may occur in distinct waves, intervals with high release of thefirst API are followed by intervals with low or no release. Further, theAPI can be administered in several phases over time. These phases (andin particular their onset) can be controlled by controlling thearrangement of the areas of increased concentration within the drugdelivery system, by choosing or adjusting the respective printingprofiles during screen-printing.

Further preferred, the pastes are screen-printed such that in theresulting drug delivery system the variation of the concentration of thefirst API throughout the system is at least 5%, further preferred atleast 10%, further preferred at least 15%, further preferred at least20%, further preferred at least 25%, further preferred at least 30%,further preferred at least 35%, further preferred at least 40%, furtherpreferred at least 45%, further preferred at least 50%, furtherpreferred at least 55%, further preferred at least 60%, furtherpreferred at least 65%, further preferred at least 70%, furtherpreferred at least 75%, further preferred at least 80%, furtherpreferred at least 85%, further preferred at least 90%, furtherpreferred at least 95%, further preferred approximately 100%. Furtherpreferred, the pastes are screen-printed such that in the resulting drugdelivery system the variation of the concentration of the first APIthroughout the system is at most approximately 100%, further preferredat most 95%, further preferred at most 90%, further preferred at most85%, further preferred at most 80%, further preferred at most 75%,further preferred at most 70%, further preferred at most 65%, furtherpreferred at most 60%, further preferred at most 55%, further preferredat most 50%, further preferred at most 45%, further preferred at most40%, further preferred at most 35%, further preferred at most 30%,further preferred at most 25%, further preferred at most 20%, furtherpreferred at most 15%, further preferred at most 10%, further preferredat most 5%. Thus, the variation of the concentration can be set in acontrolled manner, by providing a respective local arrangement of thefirst paste relative to the base paste with the screen-printingtechnique, to eventually obtain a desired controlled administration ofthe first API with the resulting drug delivery system. The variation ofthe concentration of the first API may be defined as the difference ofthe maximum concentration and the minimum concentration of the API inthe drug delivery system. In this context, the concentration may be themass-specific concentration. The respective sampling volume formeasuring the concentration may be any suitable volume, and may forexample be of 1 μm³. For example, if the highest concentration in asampling volume in the drug delivery system is of about 80%, and thelowest concentration in a sampling volume in the drug delivery system isof about 10%, then the variation may be 70%. Thus, for example,throughout the drug delivery system, the concentration of the first APImay be at least 10%, and at a central part of the drug delivery system,the concentration of the first API may increase to 80%.

Further preferred, the pastes are screen-printed such that in theresulting drug delivery system the concentration profile of the firstAPI is such that upon application of the system, the first API isreleased from the system at a predetermined release profile, whichfurther preferred comprises a section with a release at a constant rate.Accordingly, the first paste may be arranged such within the base pastedue to the particular screen-printing profiles that upon application ofthe resulting drug delivery system, and upon dissolution of the (cured)base paste and (cured) first paste, a particular release profile of theAPI is obtained, with a constant release section in a preferredembodiment.

Particularly preferred, the pastes are screen-printed such that in theresulting drug delivery system the first paste is arranged in the basepaste such that upon dissolution of the drug delivery system or the(cured) pastes, the total amount of the first API at an outer surface ofthe drug delivery system remains approximately constant for apredetermined time, wherein the predetermined time is preferably in therange of 1 second up to 180 days. For example, printing profiles may bechosen which allow for screen-printing the first paste such that theamount of printed first paste increases towards central parts of thedrug delivery system only. The person skilled in the art understandsthat depending on the respective application and the form of the drugdelivery system, rather longer or rather shorter release periods may beapplicable. For example, if the drug delivery system is produced in formof an implant, the API may be release during an extended period of up to180 days. If the drug delivery system is produced in form of a tablet,for example, the API may be released during a period of up to 12 hours.Accordingly, further preferred, the predetermined time of approximatelyconstant release is in the range of 5 seconds to 24 hours, furtherpreferred 10 seconds to 12 hours, further preferred, 1 minute to 6hours, further preferred 10 minutes to 1 hour. Accordingly, in theexemplary case of a spherical tablet, a gradient of the concentration ofthe first API may point inwards, so that the amount of API at thesurface of the drug delivery system remains constant when the drugdelivery system is dissolving, i.e. when the volume and surface of thesystem shrinks. Hence, the first paste may be arranged such thateventually the concentration of the first API depends on the distance tothe surface of the drug delivery system. Accordingly, by inhomogeneouslyarranging the first paste in the base paste with the screen-printingtechnique, a constant release of the first API can be set.

Further preferred, the pastes are screen-printed such that in theresulting drug delivery system the concentration profile of the firstAPI is such that upon application of the system, the first API isreleased at two or more dosages, wherein release of the first API at oneof the dosages starts preferably 1 second to 10 days (the upper valuemay for example apply if the drug delivery system is produced in theform of an implant), more preferably 2 seconds to 1 day, more preferably5 seconds to 12 hours, more preferably 10 seconds to 6 hours, morepreferably 20 seconds to 2 hours, more preferably 1 minute to 1 hour,and most preferred 10 minutes to 30 minutes before release of the firstAPI at another one of the dosages. For example, printing profiles may bechosen such that the first paste is provided at several, separatedlocations towards a center of the drug delivery system. Thus, forexample, if the drug delivery system is provided in form of a tablet,and upon oral administration of the tablet, the first API may bereleased at a first dosage shortly after administration, before thefirst API is released at a second dosage at a later time. The dosagesmay be uniform or may vary among each other. Any duration of release ofan API mentioned herein may be measured by means of dissolution tests,for example according to USP-Guideline “General Chapter <711>Dissolution”.

In a further preferred embodiment, the pastes are screen-printed suchthat in the resulting drug delivery system the base paste envelops thesystem and the first paste is not arranged at an outer face of thesystem. Accordingly, the first paste comprising the first API may beprovided such that it cannot be accessed from the outside, at leastprior to the application of the drug delivery system. Thus, the firstAPI can be effectively sealed from the environment, reducing the risk ofcontamination. Furthermore, if for example produced in form of a tablet,the dissolution of the first paste is delayed upon oral administration,as the base paste has to (at least partially) dissolve first. Thus, adelayed administration of the first API can be obtained. Preferably, thedrug delivery system is produced such that release of the first APIstarts 1 second to 1 day, further preferred, 10 seconds to 12 hours,further preferred 30 seconds to 6 hours, further preferred 1 minute to 4hours, further preferred 10 minutes to 2 hours, further preferred 30minutes to 1 hour after application of the drug delivery system.

In a further preferred embodiment, the method further comprises thesteps of screen-printing a second paste separate to the base paste andthe first paste, and curing the second paste. The second paste maycomprise a therapeutically effective amount of a second activepharmaceutical ingredient. Accordingly, the method allows for producinga drug delivery system characterized by a controlled administration ofseveral APIs in particular applications. The APIs may interact afterdissolution of the respective paste, and may thereby provide for asynergetic effect in the body. The first and second API may differ inform as well as in concentration. Preferably, the (cured) second pasteis soluble in body fluids. The respective provisions given withreference to the first paste and the base paste similarly apply here.

The person skilled in the art understands that the provisions givenherein with regard to the screen-printing and curing steps of the basepaste and first paste, as well as the provisions regarding the first APImay similarly apply in an analogous manner to the second paste and thesecond API. The person skilled in the art understands that the methodmay comprise further steps of screen-printing and curing further pastescomprising further active pharmaceutical ingredients, e.g. a third pastecomprising a third API, a fourth paste comprising a fourth API, and soon.

Particularly, the pastes are screen-printed such that a resulting planarlayer of the drug delivery system comprises all of the cured base pasteand the cured first paste and the cured second paste. Accordingly, aplanar layer of the resulting drug delivery system may comprise thecured base paste, and the cured first paste separate to the base paste,and the cured second paste separate to the base paste and the firstpaste. Thus, all the (cured) pastes can be differentiated from another,as no homogeneous mixture is provided.

Further preferred, the planar layer of the drug delivery system isproduced by screen-printing and curing the base paste to partially formthe planar layer, screen-printing and curing the first paste separate tothe base paste to partially form the planar layer, and screen-printingand curing the second paste separate to the base paste and the firstpaste to partially form the planar layer. Preferably, by producing theplanar layer, the pastes are not screen-printed in an overlappingmanner. Thus, by screen-printing and curing the base paste, a part ofthe resulting planar layer may be formed. A further part of theresulting planar layer may then be formed by screen-printing and curingthe first paste. A further part of the resulting planar layer,preferably the remaining part of the resulting planar layer, may then beformed by screen-printing and curing the second paste. For example, theresulting planar layer may thus comprise areas where only the base pasteis arranged (for example at outer regions of the layer), areas whereonly the first paste is arranged (for example at inner regions of thelayer), and areas wherein only the second paste is arranged (for exampleat intermediate regions of the layer). The pastes must not formcontinuous areas, but can form separate areas, i.e. “islands”.

Preferably, the pastes are screen-printed such that in the resultingdrug delivery system the (cured) second paste is inhomogeneouslyarranged in the (cured) base paste. Thus, the release of the first APIand the second API from the drug delivery system can be controlled alsorelatively to each other by controlling the inhomogeneous arrangement ofthe respective first and second pastes in the base paste. The aboveexplanation with regard to the inhomogeneous arrangement also applieshere.

Further preferred, the pastes are screen-printed such that in theresulting drug delivery system a concentration profile of the first APIthroughout the drug delivery system is different than a concentrationprofile of the second API throughout the drug delivery system. Forexample, printing profiles may be chosen such that the amount ofscreen-printed first paste increases towards a center of the drugdelivery system and the amount of screen-printed second paste decreasestowards the center of the drug delivery system. Accordingly, the drugdelivery system can be designed and produced such that the first API andthe second API are released to the body at different dosages.

Further preferred, the pastes are screen-printed such they areeventually arranged in a discontinuous manner within the resulting drugdelivery system such that the first active is released for a distinctperiod of time upon the start of the dissolution of the drug deliverysystem, which typically occurs from the periphery. Similar to an onionskin type arrangement, the layer with the first paste may be adjacent toanother layer containing either no API or the second API, for example.By varying parameters like the thickness of the layers, theircomposition, and the distribution of the APIs within the layers, therelease of the APIs may be controlled.

Further preferred, the pastes are screen-printed such that in theresulting drug delivery system the first paste and the second paste arearranged such that upon application of the drug delivery system, releaseof the first API starts before release of the second API. For example,printing profiles may be chosen such that the second paste is printedcloser to the center of the drug delivery system, while the first pasteis printed further to the edge of the drug delivery system. The releaseof the first API may further preferred start 1 second to 10 days (theupper value may for example apply if the drug delivery system isproduced as an implant), more preferably 2 seconds to 1 day, morepreferably 5 seconds to 12 hours, more preferably 10 seconds to 6 hours,more preferably 20 seconds to 2 hours, more preferably 1 minute to 1hour, and most preferred 10 minutes to 30 minutes before release of thesecond API. Accordingly, due to the particular inhomogeneous ordiscontinuous arrangement of the first and second pastes in the basepaste, preferably with regard to the dissolution direction, it can becontrolled at what time the respective first and second APIs arereleased relative to one another. Depending on the spatial arrangementof the first and second APIs within the layers, the release of the twoAPIs may be separated by a defined time interval or the release of thefirst API may continue when the release of the second API starts.Thereby, particular synergetic effects of the APIs may be obtained.Generally, the APIs may be released to the body within hours, days andmonths, depending on the individual form of application.

Preferably, the pastes are screen-printed such that in the resultingdrug delivery system the first paste and the second paste are arrangedsuch that upon application of the drug delivery system, a releaseprofile of the first API differs from a release profile of a second API.For example, the first API may be released at a rather constant rate,while the second API may be released intermittently. This allows fordesigning an elaborate drug delivery system.

In a preferred embodiment, the total amount of the first API in thefirst paste in the resulting drug delivery system is between 1 μg and100 g, preferably between 10 μg and 10 g, more preferably between 100 μgand 1 g, more preferably between 500 μg and 500 mg, more preferablybetween 1 mg and 100 mg, more preferably between 10 mg and 50 mg. Theperson skilled in the art understands that any description with regardto the first API may also apply to a possible second or further APIsprovided in a second or further pastes of the drug delivery system.

In a further preferred embodiment, one or more of the pastes comprises aceramic, metal, polymer (preferably polymer acrylate) and/or minerals.

In a preferred embodiment, one or more of the pastes comprises adisintegration agent, which may facilitate dissolution of the respective(cured) paste. The disintegration agent may comprise cellulose(preferably microcrystalline cellulose), croscarmelose sodium,crospovidone, starches (preferably modified starches), cross-linkedplyvinylpyrrolidone, sodium starch glycolate, and/or sodiumcarboxymethylcellulose.

Preferably, one or more of the pastes may comprise one or moreconstituents selected from the following list: colorant, sweetener,flavor, antimicrobial preservative (e.g. sorbic acid, benzoic acid,parabens, scrose, benzalkonium chloride), chemical stabilizers which maybe used to increase the chemical stability of the API (e.g. antioxidantssuch as ascorbic acid or sodium metabisulfite, chelators such asethylenediaminetetraacetic acid), viscosity modifiers which may be usedto reduce the sedimentation of particles (e.g. polymeric materials orinorganic materials such as clay), cellulosic materials which may beused as viscosity enhancers in suspensions (e.g. cellulose, celluloseethers, alginic acid).

Preferably, one or more of the pastes may comprise one or moreexcipients selected from the following list: filler (e.g. lactose,sucrose, glucose, mannitol, sorbitol, calcium carbonate, cellulose),solution binder (e.g. gelatin, polyvinylpyrrolidone, cellulosederivative, polyethylene glycol), dry binder (e.g. cellulose,polyethylene glycol, methylcellulose), glidant (e.g. silica, magnesiumstearate, talc).

In a preferred embodiment, the first paste is screen-printed to form ageometrical shape. The shape may preferably be a tube (which may be ahollow tube), a spot (which may be a local, small cluster oragglomeration), an oval (e.g. in the shape of an open circle orellipse), a plate, and/or a polygon (e.g. in the shape of a square).Thus, the first paste may be provided in such a shape that a desiredrelease of the first API is obtained, possibly even with regard tofurther APIs provided in further pastes of the system. Within theparticular geometrical shape, the concentration of the API may vary.

In a preferred embodiment, the resulting drug delivery system is in theform of a tablet, a capsule, a disc, a film, an implant, a subcutaneousimplant, a patch, pellets or granules. Thus, the drug delivery systemproduced according to the present invention may have various forms, andthereby allow for a desired administration and desired release of an APIaccording to the particular therapeutic application.

Preferably, the pastes are screen-printed such that the resulting drugdelivery system features a structured surface. For example, the printingprofiles may be chosen such that protrusions and recesses are formingthe surface of the resulting drug delivery system. Thereby, the surfaceof the resulting drug delivery system can be enlarged, so thateventually a high release of the respective API can be provided for.

It will be appreciated that the drug delivery system produced accordingto the present invention is not limited to a particular API. Generally,any suitable API, which can be provided in a respective paste to beinhomogeneously arranged within a base paste, can be used. For example,the API may be any of anti-infectives, anti-inflammatories, cardioactiveagents, neuroleptic agents, or even nutritional agents. The skilledperson understands that this list is not limiting. Further, the drugdelivery system produced according to the present invention may comprisefurther components or substances, for example additives or the like.

In a preferred embodiment, the first API may be any of anthelminticagents, narcotics and narcotic antagonists; anti-histamines, adrenergicagents, adrenergic blockers sedative hypnotics, CNS agents, analeptics,antiparkinson agents, steroids, coronary vasodilators, anticoagulants,antihypercholesterolemics, antibiotics, antifungal agents, antiviralagents, bone growth promotants, anticancer agents, vitamins,antiinflammatory agents, or antihypertensive agents. In a preferredembodiment, the first API may comprise Pregabalin, Lurasidon, Fentanyl,Rivaroxaban, Sildenafil/Tadalafil, Desatinib, Sorafenib, Varenicline,Memantine, Dexlansoprazole, Sunitinib, Nebivolol, Zolmitriptan,Sitagliptin, Lacosamid, Desvenlafaxin, Lenalidomid,Ledipasvir/Sofosbuvir, Aripiprazole, Levodopa, orOndansetron/Granisetron. Again, the skilled person understands that thislist is not limiting.

The present invention further relates to a drug delivery system producedwith a method as described herein.

Furthermore, the present invention relates to a system for producing adrug delivery system. The system (or production system) therebycomprises means for producing a drug delivery system in a manner asdescribed herein. A production system for producing a drug deliverysystem according to the present invention may thereby comprise means forscreen-printing a base paste, means for curing the base paste, means forscreen-printing a first paste separate to the base paste, and means forcuring the first paste. Again, the first paste thereby comprises atherapeutically effective amount of a first API. The person skilled inthe art understands that within the concept of the present invention,the production system may further comprise means for screen-printing asecond paste comprising a therapeutically effective amount of a secondAPI, for example.

4. BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

In the following, the present invention will be described with referenceto the enclosed figures. Thereby, similar features are provided withequal reference signs. It shows:

FIGS. 1(a)-(d) illustrate the operation of a part of a production systemfor producing a drug delivery system according to the present invention;

FIG. 2 a first design of a production system for producing a drugdelivery system according to the present invention;

FIG. 3 a second design of a production system for producing a drugdelivery system according to the present invention;

FIG. 4 a third design of a production system for producing a drugdelivery system according to the present invention;

FIG. 5 a design of a drug delivery system produced according to thepresent invention and the respective concentration profile;

FIG. 6 several API release profiles of drug delivery systems producedaccording to the present invention wherein graph (1) represents therelease profile when the API is homogeneously distributed throughout thedrug delivery system, graph (2) represents the release profile when theAPI is arranged at an edge of the drug delivery system and graph (3)represents the release profile when the API is accumulated at a centralpart of the drug delivery system;

FIG. 7 further designs of drug delivery systems (a)-(i) producedaccording to the present invention comprising a base paste, pastes A-D,and an additive;

FIG. 8 further designs of drug delivery systems (i)-(m) producedaccording to the present invention;

FIG. 9 another design of a drug delivery system produced according tothe present invention; and

FIG. 10 a structured drug delivery system produced according to thepresent invention.

FIG. 1 illustrates a part of a production system for producing a drugdelivery system according to the present invention. As can be seen, ascreen 10 is provided, which allows for screen-printing pastes in thesense of the present invention, for example a base paste. Therefore, thescreen 10 comprises a respective mask 11, which masks particular partsfor screen-printing a desired pattern, according to a respectiveprinting profile. Furthermore, the screen 10 comprises a blade 13 whichcan draw the material or paste 12 to be printed over the screen, and inparticular over the mask 11.

As can be seen in section a) of FIG. 1, a movable platform 20 isprovided beneath the screen 10. A particular built 40 is already presenton the platform 20, which may have been produced layer-by-layeraccording to the present invention.

As can be seen in section b) of FIG. 1, the blade 13 can draw the paste12 along the screen 10, such that a further layer of the paste 12 isscreen-printed onto the built 40. As the mask 11 masks several parts,the paste 12 is printed only at particular locations on the built 40.Thus, the arrangement of the paste 12 within the resulting drug deliverysystem can be precisely controlled.

Afterwards, as can be seen in section c) of FIG. 1, the screen 10 isuplifted, and the platform 20 with the built 40 comprising theadditional layer of a screen-printed paste moves horizontally to placethe built 40 underneath a dryer 30. By means of this dryer 30, thescreen-printed layer is cured. Thereby, the printed paste may harden.

Afterwards, the platform 20 may be moved to another screen at anotherprinting station, to complete further parts of the layer byscreen-printing and curing further pastes.

After completion of the layer, the platform may be returned to theillustrated printer and screen 10, as illustrated in section d) of FIG.1, to print the respective paste 12 on top of the built 40. The heightof the platform 20 is lowered by an amount which corresponds to thethickness of the previously build layer, and the screen 10 is moved toits lower printing position so that a further layer can be provided ontop of the cured layer.

FIGS. 2-4 show different design concepts of production systems forproducing a drug delivery system according to the present invention. InFIG. 2, two screen-printers 10 a, 10 b are arranged with a dryer 30 inbetween. With the printer 10 a, a base paste according to the presentinvention may be printed, which may then be cured by means of the dryer30, and then a first paste may be printed by means of printer 10 b atparts not covered by the base paste. Afterwards, also the first pastemay be cured with the dryer 30, before the built is moved back to thefirst printer 10 a for starting the production of a new layer. Bychanging the meshes or printing profiles of the printers 10 a, 10 b, thethree-dimensional layout of the pastes in the resulting drug deliverysystem can be modified.

According to the concept of FIG. 3, five printers 10 are arranged inaddition to a single dryer 30. With each of these printers, differentpastes may be screen-printed to eventually form a single, continuouslayer, which may then be cured in one step by means of the single dryer30. Afterwards, a new layer may be produced on top thereof.

According to the design of FIG. 4, several printers 10 may be arrangedtogether with several dryers 30. Thereby, three successive printers 10may print a first complete planar layer, which is then cured with arespective dryer 30, before a further planar layer is printed on top,which may differ from the previously printed and cured layer. Thisprocedure may be reiterated with the further printers and dryers, aswill be appreciated by the person skilled in the art.

FIG. 5 illustrates a design of a drug delivery system produced accordingto the present invention. Thereby, a planar layer of the drug deliverysystem is shown, which may extend through the drug delivery system.Therein, the paste comprising the API and the base paste are arranged ona grid-like structure, with each “pixel” defined either by the API pasteor the base paste. As can be seen, the two pastes are arranged such thatthe density of the “API-pixels” is higher at a central part of the drugdelivery system. This is also apparent from the API concentrationprofile, which is also illustrated in FIG. 5. The profile features apeak of high API concentration at the center of the system, and low APIconcentration at the edges of the system. The transition from the lowAPI concentration at the edges to the high API concentration at thecenter is smooth, as it does not feature any abrupt steps. With such adrug delivery system, the release profile of the drug delivery systemupon dissolution of the two pastes is adjusted or configured in adesired manner.

FIG. 6 shows the release profile of a common drug delivery system with ahomogeneously distributed API (graph (1) in FIG. 6), as well as tworelease profiles of drug delivery systems produced according to thepresent invention (graphs (1), (2), and (3) in FIG.3).

Regarding graph (1) in FIG. 6, the design of the respective drugdelivery system is such that the API is homogeneously distributedthroughout the drug delivery system. This principle of homogeneity,which is the key feature of common prior art drug delivery systems,derives from the corresponding manufacturing processes. Upon dissolutionof classical drug delivery systems, the respective API is released. Dueto the dissolution characteristics of the homogeneous system and theshape of the drug delivery system, a particular and fixed releaseprofile is obtained. As can be seen from graph (1) in FIG. 6, therelease of the API increases gradually over time, reaches a maximum, andthereafter decreases gradually.

Due to the inhomogeneous arrangement of the API according to the presentinvention, different release profiles can be obtained. The designassociated with graph (2) in FIG. 6 is different from that associatedwith graph (1) in FIG. 6, as the API is arranged at an edge of the drugdelivery system. Hence, the principle of a homogeneous distribution ofthe API in the drug delivery system is suspended, as the API isinhomogeneously arranged in the drug delivery system, being providedhere with a high concentration at the edge of the drug delivery system.The concentration of the API smoothly decreases towards the center ofthe drug delivery system. Upon application of the drug delivery systemassociated with graph (2) of FIG. 6, the release of the API is ratherhigh in the beginning and then decreases gradually. Such a high initialAPI release may be beneficial for particular applications, as will beappreciated by the person skilled in the art.

In the design associated with graph (3) in FIG. 6, the API isaccumulated at a central part of the drug delivery system. Thus, theconcentration of the API is highest at the center of the system, and thegradient of the concentration points from the edge of the system to itscenter. As can be seen from the respective graph (3) in FIG. 6, therelease increases approximately gradually over a prolonged period oftime, and the maximum release rate is delayed in time as compared to thecommon design. In comparison to the common design, the release of theAPI can be considered to be more constant, for an extended period oftime. Such a release profile may be beneficial for particularapplications, as will be appreciated by the person skilled in the art.

FIG. 7 illustrates nine design options for drug delivery systemsproduced according to the present invention. As can be seen, all thesedesigns comprise a base paste, which forms the overall body of therespective drug delivery system (DDS) and can be considered as a matrix,within which further pastes may be arranged. These further pastes arelabeled as paste A, paste B, paste C and paste D, and may each comprisea therapeutically effective amount of a separate active pharmaceuticalingredient (API). Thus, any of the pastes A-D may be considered as afirst paste within the context of the present invention. The base pasteand the pastes A-D are soluble in body fluids.

The design of DDS (a) in FIG. 7 has a round shape. DDS (a) may be in aform of a tablet, a disc or the like. It has a particular diameter D,which may be, for example, 15 mm. Within the base paste of the DDS (a),a first paste A comprising a first API, a second paste B comprising asecond API and a third paste C comprising a third API are provided. Ascan be seen, the respective APIs are not distributed homogeneouslythrough the drug delivery system, but are arranged inhomogeneouslywithin the base paste, as the pastes A, B, C are provided at particularpositions within the drug delivery system. The pastes A, B, C areprovided in a polygonal shape, with a hexagonal cross section.

Upon application of DDS (a) and dissolution thereof, the base pastedissolves first, as the dissolution may begin at the edge of the system.After a particular period of time, paste C and then paste B start todissolve, thereby releasing the respective APIs. Later on, paste Aeventually starts to dissolve, thereby releasing the respective firstAPI provided therein. Thus, due to the particular arrangement of thepastes in the drug delivery system, the different APIs are released atdifferent stages at different dosages after application of the drugdelivery system. Due to the particular arrangement of the differentpastes within DDS (a), each API is released at a particular time afterapplication of the drug delivery system, with a particular andindividual, API-specific release profile.

The design of DDS (b) in FIG. 7 is formed as a tablet, with a height of,for example, 2.5 mm, and a diameter of again 15 mm. Two pastes B and Ccomprising each an API are provided within the base paste in aninhomogeneous manner according to the present invention. Uponapplication of the drug delivery system, particular release profiles ofthe APIs contained in pastes B and C are obtained, which may featuresmooth transitions between phases of increased release.

The design of DDS (c) in FIG. 7 is similar to that of DDS (a), howevercomprising, beside the base paste, only two pastes B and C comprisingeach an API. Upon application of the drug delivery system, particularrelease profiles of the APIs contained in pastes B and C are obtained,which may feature smooth transitions between phases of increasedrelease.

In the design of DDS (d) in FIG. 7, two pastes with APIs are provided ina tube-like shape. Similarly, the pastes may also be provided in form ofstacked plates.

DDS (e) in FIG. 7 has a design where the pastes comprising APIs areprovided as spots within the base paste. Upon application of the drugdelivery system, particular release profiles of the APIs contained inpastes B and C are obtained, which may feature smooth transitionsbetween phases of increased release.

DDS (f) in FIG. 7 has a design of a particular heights of, for example,25 mm, wherein only one paste comprising an API is arrangedinhomogeneously in the base paste, in a tube-like manner. Similarly, thepaste may also be provided in form of plates.

DDS (g) in FIG. 7 is similar to DDS (e), however the pastes comprisingAPIs are arranged in a more random manner. Upon application of thesystem, particular release profiles of the APIs contained in pastes Band C are obtained, which may feature smooth transitions between phasesof increased release.

DDS (h) in FIG. 7 has a design, where the pastes comprising the APIs areprovided or arranged in the form of circles within the base paste. Uponapplication of the drug delivery system, the base paste and the firstpaste dissolve in an alternating manner, such that the first API isreleased intermittently, for example in a rather periodic manner. Afterthe first API is completely released, the second paste startsdissolving, thereby releasing the second API. As can be seen, thecircles of paste A are not concentric, and are not having a uniformthickness. Due to this particularly inhomogeneous arrangement, aparticular release profile is obtained, which may feature smoothtransitions between phases of increased release.

DDS (i) in FIG. 7 has a design where a paste comprising an API isprovided in a particular pattern within a matrix of additives, which isarranged in the base paste.

FIG. 8 shows further design options for a drug delivery system producedaccording to the present invention. The overall shape of the system isthat of a round disc with a diameter of 5-25 mm, preferably 20 mm or 15mm, and a thickness of 0.5-15 mm, preferably 2 mm or 6 mm. A cut intothe tablets is provided to allow for a view on the arrangement of thepastes in the tablets.

The design of DDS (j) in FIG. 8 has a first paste comprising a first APIprovided at the central part of the tablet, being surrounded by a basepaste, while the entire tablet is coated with a coating. The coating maybe a hydrophilic coating, or may provide entericcoated properties, forexample. The concentration of the API within the tablet is highest atthe center of the tablet. The concentration profile of the API is suchthat it comprises a smooth transition from the edge of the tablettowards the center of the tablet.

The design of DDS (k) in FIG. 8 has a first paste comprising a first APIand a second paste comprising a second API being provided within a basepaste. Again, also a coating is provided. The second paste is arrangedin the form or a sphere, and the concentration of the second API ishighest on the surface of the sphere, decreasing smoothly towards thecenter of the sphere. Within the sphere formed of the second paste, thefirst paste is provided. Thus, upon application of the tablet anddissolution of the pastes, the second API is released prior to the firstAPI, and during a transition period, both APIs are released.

The design of DDS (l) in FIG. 8 has two different APIs, with the secondAPI being provided at a central part of the tablet, and the first API isprovided around the second API. At an interface region between bothAPIs, there is an overlap of the APIs, such that in this interfaceregion, both APIs are arranged. Thereby, a smooth crossover is achieved.Furthermore, layers are provided, extending through the system, whichmay be hydrophobic layers.

The design of DDS (m) in FIG. 8 does not have a coating. An API isinhomogeneously arranged in the tablet, such that areas or regions withdifferent concentrations of the API are formed.

FIG. 9 illustrates a further design option for a drug delivery systemaccording to the present invention. The system is provided in aspherical shape, and has a hydrophobic coating. The coating compriseshydrophilic pores with sizes in the range of 1 μm to 500 μm. Inside thedrug delivery system, there is provided a base paste and three differentactive pharmaceutical ingredients, API A, API B, and API C. The API C isprovided at a central part of the drug delivery system with a peripheralpattern. The other two APIs A and B surround API C. Thereby, API B isprovided as a hollow sphere, with a homogeneous distribution of the API.Furthermore, API A is inhomogeneously distributed, surrounding the APIC. Thereby, the concentration of API A diminishes towards an edge of theillustrated drug delivery system.

FIG. 10 illustrates a cross-section of a drug delivery system accordingto the present invention. As can be depicted, the surface of the drugdelivery system is structured, as six protrusions and respectiverecesses in between are formed on one side thereof. By increasing thesurface in this manner, the dissolution of the drug delivery system andthus the release of the API can be enhanced. The person skilled in theart understands that the entire surface of the drug delivery system, oronly one or several parts thereof may be structured.

Therefore, the person skilled in the art understands that with the drugdelivery system produced according to the present invention, aparticular inhomogeneous distribution of one or more APIs within thedrug delivery system can be arranged in order to provide a desire torelease API(s). The person skilled in the art understands that a promptrelease or a delayed release of an API can be obtained. Furthermore, itis possible to release a particular single API at different dosages overa prolonged period of time, for example intermittently, therebyobtaining a release of the API in phases.

Furthermore, it is possible to obtain a release of different APIs indistinct phases with a single, novel drug delivery system. For example,it is possible to design the drug delivery system such that a first APIis released before a second API is released. Examples for such drugdelivery systems integrating two or potentially more APIs includegastroprotective agents such as proton pump inhibitors or antihistaminesand non-steroidal anti-inflammatory substances such as ibuprofen ordiclofenac. Another example would be the combination of antiemetics(e.g. ondansetron, domperidon) and analgesics, especially those actingon structures of the central nervous system (e.g.,tramadolhydrochloride). Another example would be the combination ofCarbidopa and Levodopa, thus an agent that prevents the degradation ofthe pharmaceutically active ingredient. The person skilled in the artunderstands that the release of these two APIs may provide particularsynergetic effects. Furthermore, controlled release could mean mimicryof physiology, e.g. a Cortisone therapy whereas the drug delivery systemis administered at 10:00 μm, preferably releasing the steroid 6 hourslater. As the steroid is desirably administered at 4:00 am, it ispossible to administer the steroid with the drug delivery systemaccording to the present invention, which can be designed such that itis ingested in the previous evening, but the respective API is releasedat the desired time during the night. Similarly, with the drug deliverysystem according to the present invention, it is possible to ensure aproper administration of antibiotics in phases, for example, over aprolonged period of time (e.g. over days). Thus, the negative effects ofpatients disregarding the prescribed administration routine can bereduced.

The person skilled in the art further understands that the usage of thescreen-printing technique allows for the production of such elaboratedrug delivery systems with high quality, and at great quantities.Thereby, the drug delivery system can be produced in a mass productioncontext.

The design options resulting from the concept of producing aninhomogeneous arrangement of one or more APIs in a drug delivery systemare numerous. The person skilled in the art understands that the aboveexamples can be combined to obtain further elaborate designs withrelease profiles optimized to the particular application or therapy.

The invention claimed is:
 1. A method for producing a drug deliverysystem, the method comprising: screen-printing a base paste; curing thebase paste; screen-printing a first paste separate to the base paste;curing the first paste; wherein the first paste comprises atherapeutically effective amount of a first active pharmaceuticalingredient, API, wherein the base paste and the first paste are solublein body fluids such that the resulting drug delivery system is solublein body fluids, wherein the pastes are screen-printed such that in theresulting drug delivery system the first paste is inhomogeneouslyarranged in the base paste, wherein the pastes are screen-printed suchthat the base component is provided as a three-dimensional body and theseparate first component is inhomogeneously arranged throughout the basecomponent along the three dimensions, wherein the pastes arescreen-printed such that in the resulting drug delivery system theconcentration of the first API varies throughout the drug deliverysystem, wherein the concentration profile of the first API is such thatupon application of the drug delivery system the release of the firstAPI occurs at a varying rate, wherein the first API is not selected froma list comprising anthelmintic agents, narcotics and narcoticantagonists, anti-histamines, adrenergic agents, adrenergic blockers,sedative hypnotics, CNS agents, analeptics, antiparkinson agents,steroids, coronary vasodilators, anticoagulants,antihypercholesterolemics, antibiotics, antifungal agents, antiviralagents, anticancer agents, antiinflammatory agents, antihypertensiveagents, Pregabalin, Lurasidon, Fentanyl, Rivaroxaban,Sildenafil/Tadalafil, Desatinib, Sorafenib, Varenicline, Memantine,Sunitinib, Nebivolol, Zolmitriptan, Lacosamid, Desvenlafaxin,Lenalidomid, Ledipasvir/Sofosbuvir, Aripiprazole, or Levodopa.
 2. Themethod of claim 1, wherein the drug delivery system is producedlayer-by-layer.
 3. The method of claim 1, wherein the base paste and thefirst paste are screen-printed such that a resulting planar layer of thedrug delivery system comprises both the base paste and the first paste.4. The method of claim 3, wherein the planar layer of the drug deliverysystem is produced by: screen-printing and curing the base paste topartially form the planar layer, screen-printing and curing the firstpaste separate to the base paste to partially form the planar layer. 5.The method of claim 4, wherein after finishing the production of theplanar layer, a further planar layer is produced on top of the finishedplanar layer.
 6. The method of claim 1, wherein the base paste isscreen-printed at a screen-printer, and wherein the first paste isscreen-printed using a separate screen-printer.
 7. The method of claim1, wherein the base paste and the first paste are cured with a sharedcuring device.
 8. The method of claim 1, wherein the pastes arescreen-printed such that in the resulting drug delivery system theconcentration of the first API is highest at a center, at an edge or atan intermediate region of the drug delivery system.
 9. The method ofclaim 1, wherein the pastes are screen-printed such that in theresulting drug delivery system a gradient of the concentration of thefirst API increases towards or increases away from a center of the drugdelivery system.
 10. The method of claim 1, wherein the pastes arescreen-printed such that in the resulting drug delivery system aconcentration profile of the first API throughout the drug deliverysystem comprises a smooth transition to an area of increasedconcentration.
 11. The method of claim 1, wherein the pastes arescreen-printed such that in the resulting drug delivery system theconcentration profile of the first API throughout the drug deliverysystem comprises more than one area of increased concentration.
 12. Themethod claim 1, wherein the pastes are screen-printed such that in theresulting drug delivery system the variation of the concentration of thefirst API throughout the drug delivery system is at least 5%.
 13. Themethod of claim 1, wherein the pastes are screen-printed such that inthe resulting drug delivery system the variation of the concentration ofthe first API throughout the drug delivery system is at mostapproximately 100%.
 14. The method of claim 1, wherein the pastes arescreen-printed such that in the resulting drug delivery system theconcentration profile of the first API is such that upon application ofthe drug delivery system, the first API is released from the drugdelivery system at a predetermined release profile, which comprises asection with a release at a constant rate.
 15. The method of claim 1,wherein the pastes are screen-printed such that in the resulting drugdelivery system the concentration profile of the first API is such thatupon application of the drug delivery system, the first API is releasedat two or more dosages, wherein release of the first API at one of thedosages starts preferably 1 second to 10 days.
 16. The method of claim1, wherein the pastes are screen-printed such that the base pasteenvelops the resulting drug delivery system and the first paste is notarranged at an outer face of the resulting drug delivery system.
 17. Themethod of claim 1, further comprising the steps of: screen-printing asecond paste separate to the base paste and the first paste; curing thesecond paste; wherein the second paste comprises a therapeuticallyeffective amount of a second API.
 18. The method of claim 17, whereinthe pastes are screen-printed such that a resulting planar layer of thedrug delivery system comprises the base paste and the first paste andthe second paste.
 19. The method of claim 18, wherein the planar layerof the drug delivery system is produced by: screen-printing and curingthe base paste to partially form the planar layer, screen-printing andcuring the first paste separate to the base paste to partially form theplanar layer screen-printing and curing the second paste separate to thebase paste and the first paste to partially form the planar layer. 20.The method of claim 17, wherein the second paste is soluble in bodyfluids.
 21. The method of claim 17, wherein the pastes arescreen-printed such that in the resulting drug delivery system thesecond paste is inhomogeneously arranged in the base paste.
 22. Themethod of claim 17, wherein the pastes are screen-printed such that inthe resulting drug delivery system the concentration profile of thefirst API throughout the drug delivery system is different than theconcentration profile of the second API throughout the drug deliverysystem.
 23. The method of claim 17, wherein the pastes arescreen-printed such that upon application of the resulting drug deliverysystem, release of the first API starts before release of the secondAPI, wherein the release of the first API starts 1 second to 10 days.24. The method of claim 17, wherein the pastes are screen-printed suchthat upon application of the resulting drug delivery system, a releaseprofile of the first API differs from a release profile of the secondAPI.
 25. The method of claim 1, wherein the first paste isscreen-printed to form a geometrical shape, the shape being a tube, aspot, an oval, a plate, and/or a polygon.
 26. The method of claim 1,wherein the resulting drug delivery system is in the form of a tablet, acapsule, a disk, a film, an implant, a subdermal implant, a patch,pellets, or granules.
 27. The method of claim 1, wherein the first APIis selected from a list comprising bone growth promotants, or vitamins.28. The method of claim 1, wherein the first API is selected from a listcomprising Dexlansoprazole, Sitagliptin, or Ondansetron/Granisetron.